A nontoxic pain killer designed by modeling of pathological receptor conformations

作者：Spahn V; Del Vecchio G; Labuz D; Rodriguez Gaztelumendi A; Massaly N; Temp J; Durmaz V; Sabri P; Reidelbach M; Machelska H; Weber M; Stein C^*

来源：Science, 2017, 355(6328): 966-+.

DOI：10.1126/science.aai8636

Indiscriminate activation of opioid receptors provides pain relief but also severe central and intestinal side effects. We hypothesized that exploiting pathological ( rather than physiological) conformation dynamics of opioid receptor-ligand interactions might yield ligands without adverse actions. By computer simulations at low pH, a hallmark of injured tissue, we designed an agonist that, because of its low acid dissociation constant, selectively activates peripheral mu-opioid receptors at the source of pain generation. Unlike the conventional opioid fentanyl, this agonist showed pH-sensitive binding, heterotrimeric guanine nucleotide-binding protein (G protein) subunit dissociation by fluorescence resonance energy transfer, and adenosine 3',5'-monophosphate inhibition in vitro. It produced injury-restricted analgesia in rats with different types of inflammatory pain without exhibiting respiratory depression, sedation, constipation, or addiction potential.

• 出版日期2017-3-3